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Background: Microcytic anemia due to iron deficiency is the most common type of anemia in children in Israel and many parts of the world, and has been shown to have negative consequences for the cognitive performance. We aimed to examine the association between microcytic anemia at age 9-18 months and ADHD during childhood. Methods: This case-control study included healthy children aged 6-18 years at data collection (April 2020), insured by Clalit-Health-Services, and aged 9-18 months between June 2004 and December 2013, when a blood-count was performed. The study group included children diagnosed with ADHD based on the medical documentation of at least two consecutive stimulant prescriptions. A control group without any stimulant prescriptions was matched in a ratio of 1-3:1, by year of birth, sex and cultural background. Any microcytic anemia was defined as Hb < 10.5 g/dl and MCV 60-75 fl. Moderate microcytic anemia as Hb 7-9.9 g/dl. We performed a conditional-logistic-regression analysis, adjusted by socioeconomic status (SES) and year of birth. Sensitivity analysis examined this association stratified by sex, cultural background, SES and age at data collection quintiles. Results: Any microcytic anemia prevalence was lower in the ADHD group (n = 19,467) as compared to the controls (n = 39,004) (3.4 % and 4.0 %, respectively), adjusted-OR = 0.86 (95%CI: 0.78, 0.98). The prevalence of moderate microcytic anemia was similar (0.9 % vs. 1.0 %). Lower any microcytic anemia prevalence in the ADHD group was found in boys, secular-traditional Jews, and in the 4th quintile of age (12.1-13.5 years). Conclusions: We found a small inverse association between microcytic anemia at 9-18-months and ADHD during childhood, thus rejecting our hypothesis that microcytic anemia at infancy is associated with a higher prevalence of ADHD. Further studies are warranted, to examine the effects of ID and brain iron concentration on the development of ADHD in childhood.

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AIMS: To investigate the potential association of chronic use of omeprazole with the occurrence of osteoporotic fractures (OF) in community-dwelling elderly subjects. METHODS: The cohort consisted of community-dwelling residents aged >65 years registered with a large health maintenance organization in Israel between January 2002 and December 2016. Data were retrospectively collected from the electronic medical files on demographics, parameters known to be associated with OF, diagnoses of osteoporotic hip, wrist, and vertebral fractures, and chronic use of omeprazole (>11 prescriptions/year). Time to OF/death/end of study was calculated from the beginning of the study (2002). The risk of fractures in the chronic users of omeprazole was analyzed by multivariate Cox proportional hazard regression model. RESULTS: In total, 46 805 subjects were included (41% men), mean age 83.4±6.4 years, of whom 10 272 (21.9%) were chronic users of omeprazole. During 14 years of follow-up, OF were diagnosed in 414 (4.0%) omeprazole users and 1007 (2.8%) omeprazole nonusers (p < 0.001). In a Cox regression model adjusted for age and gender only, chronic use of omeprazole was associated with a 16% excess of OF. However, when parameters known to be associated with OF were entered into the multivariate Cox regression model, chronic use of omeprazole was not found to be an independent risk factor for OF, either overall (adjusted hazard ratio = 0.965, 95% confidence interval 0.86-1.08, P = .55) or specifically, in the ≥85 years age group (adjusted hazard ration = 0.780, 95% confidence interval 0.635-0.958, P < .05) in which an inverse correlation between omeprazole use and OF, was demonstrated. CONCLUSIONS: Chronic use of omeprazole was not associated with the occurrence of OF in elders.

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BACKGROUND: The association between long-term omeprazole use and gastric cancer (GC) risk is controversial. The aim of this study was to investigate the incidence of GC in elderly community-dwelling omeprazole chronic users with/without aspirin compared to non-users. METHODS: The registry of a large health management organization was searched for all community-dwelling members aged ≥65 years from January 2002 to December 2016. Data on demographics, background parameters, and chronic omeprazole and aspirin use (>11 prescriptions/year) were retrieved. Those diagnosed with new-onset GC during the study period (from January 2003) were identified. RESULTS: Of 51 405 subjects who met the inclusion criteria, 197 were diagnosed with GC during a mean follow-up period of 8.74 ±â€…4.16 years. This group accounted for 0.7% of PPI chronic users (72/11 008) and 0.3% (125/40 397) of nonusers (P < 0.001). GC risk was directly associated with omeprazole chronic use [hazard ratio (HR) 2.03, 95% confidence interval (CI): 1.51-2.73, P < 0.001] and inversely associated with aspirin chronic use (HR 0.55, 95% CI: 0.40-0.75, P < 0.001). Each year of omeprazole use increased GC risk by 9%, and each year of aspirin use decreased GC risk by 10% among omeprazole chronic users. The lowest rate of GC was found in omeprazole nonusers/ aspirin chronic users, and the highest, in omeprazole chronic users/aspirin nonusers. CONCLUSION: Higher GC rate was associated with omeprazole chronic use and inversely associated with aspirin chronic use relative to omeprazole nonuse in community-dwelling elderly.

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OBJECTIVES: Individuals with schizophrenia have more cardiometabolic comorbidities than the general population, live about twenty years less and consume more medical services. They are treated at general practitioners' clinics (GPCs) or at mental health clinics (MHCs). In this cohort study we investigated the association between patients' main treatment setting, cardiometabolic comorbidities and medical services utilization. METHODS: Demographics, healthcare services utilization, cardiometabolic comorbidities and medication prescriptions of patients with schizophrenia were retrieved from an electronic database for the period 1.1.2011 to 31.12.2012 and compared between patients treated mostly in MHCs (N = 260) and those treated mostly in GPCs (N = 115). RESULTS: GPC patients tended to be older (mean age 39.8 ± 13.7 vs. 34.6 ± 12.3 yrs., p < 0.0001), of lower socioeconomic status (42.6% vs 24.6%, p = 0.001) and have more cardiometabolic diagnoses (hypertension: 19.1% vs 10.8%, diabetes mellitus: 25.2% vs 17.0%, p < 0.05) than MHC patients. The former received more cardiometabolic disorder medications and utilized more secondary and tertiary medical services. Charlson Comorbidity Index (CCI) was higher in the GPC group than in the MHC group (1.8 ± 1.9 vs.1.2 ± 1. 6, p < 0.0001). A multivariate binary logistic regression analysis, adjusted for age, sex, SES and CCI found lower adjusted odds ratio for the MHC group versus the GPC group, of visiting an EMD, a specialist or to be hospitalized. CONCLUSIONS: The current study highlights the critical importance of integrating GPCs and MHCs, thus offering patients combined physical and mental care at a single location. More studies on the potential benefits of such integration to patients' health are warranted.

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Adherence to prescription medications is critical for both remission from schizophrenia and control of physical comorbidities. While schizophrenia with comorbid hypothyroidism is common, there is little research on adherence to hypothyroidism treatment in this population. The current study used a retrospective, matched case-control design. The cohort included 1,252 patients diagnosed with schizophrenia according to ICD-10 and 3,756 controls matched for gender, age, socioeconomic status and ethnicity without diagnosis of schizophrenia. All data were retrieved from the electronic medical database of a large health maintenance organization. Retrieved data included demographics, thyroid functionality test results and prescribed medications. Measures of adherence to therapy were used for analyses as were data from follow-ups of patients with hypothyroidism. A diagnosis of hypothyroidism was found in 299 patients, 115 of whom were also diagnosed with schizophrenia. The 184 without schizophrenia constituted the control group. No statistically significant differences were found between the two groups regarding prescriptions for L-thyroxin and TSH levels and number of TSH tests. Adherence of patients with schizophrenia to hypothyroidism treatment was found to be as good as that of individuals without a schizophrenia diagnosis.

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BACKGROUND: Prescription of psychostimulants has significantly increased in most countries worldwide for both preschool and school-aged children. Understanding the trends of chronic medication use among children in different age groups and from different sociodemographic backgrounds is essential. It is essential to distinguish between selected therapy areas to help decision-makers evaluate not only the relevant expected medication costs but also the specific services related to these areas. OBJECTIVE: This study will analyze differences in trends regarding medications considered psychobehavioral treatments and medications considered nonpsychobehavioral treatments and will identify risk factors and predictors for chronic medication use among children. METHODS: This is a retrospective study. Data will be extracted from the Clalit Health Services data warehouse. For each year between 2010 and 2019, there are approximately 1,500,000 children aged 0-18 years. All medication classes will be identified using the Anatomical Therapeutic Chemical code. A time-trend analysis will be performed to investigate if there is a significant difference between the trends of children's psychobehavioral and nonpsychobehavioral medication prescriptions. A logistic regression combined with machine learning models will be developed to identify variables that may increase the risk for specific chronic medication types and identify children likely to get such treatment. RESULTS: The project was funded in 2019. Data analysis is currently underway, and the results are expected to be submitted for publication in 2022. Understanding trends regarding medications considered psychobehavioral treatments and medications considered nonpsychobehavioral treatments will support the identification of risk factors and predictors for chronic medication use among children. CONCLUSIONS: Analyzing the response of the patient (and their parents or caregivers) population over time will hopefully help improve policies for prescriptions and follow-up of chronic treatments in children. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36756.

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INTRODUCTION: The association of anemia with dementia in elders is controversial. We examined the potential association of anemia with dementia in a large population of elders. METHODS: Historical-prospective registry-based study. Included 36,951 community-dwelling elders (65-113 years) that were followed during 2002-2012. Anemia of all kinds was defined according to Clalit Health Services (CHS) definitions: hemoglobin (HGB) <14 g/dL men, <12 g/dL women; and World Health Organization (WHO): HGB <13 g/dL men, <12 g/dL women. Anemia was categorized as mild (HGB 11-13 g/dL men, 11-12 g/dL women) or moderate-severe (HGB <8-10.9 g/dL men and women). Background data, laboratory values, and diagnosis of dementia and cognitive decline (DCD) were reviewed. RESULTS: During the 10-year follow-up period, DCD was newly diagnosed in 7,180 subjects (19.4%). Subjects with DCD had a higher rate of anemia than those without DCD. Time to development of DCD was 1.5 years shorter in those with than without anemia. On multivariate Cox regression analysis adjusted for age and sex, the hazard ratio (HR) for DCD was 1.45 (95% CI: 1.37-1.54) by CHS and 1.51 (95% CI: 1.41-1.61) WHO anemia criteria. The more severe the anemia, the greater the risk of DCD development (HGB 13-14 g/dL [men only], HR = 1.20 [95% CI: 1.09-1.32]; mild anemia, HR = 1.38 [95% CI: 1.28-1.49]; moderate-severe anemia, HR = 1.64 [CI: 1.41-1.90]). Every decrease in 1 standard deviation of HGB (1.4 g/dL) increased the DCD risk by 15%. A competing risk model has weakened the association of anemia with DCD risk. CONCLUSIONS AND IMPLICATIONS: Anemia in community-dwelling elders appears to be associated with an increased DCD risk in a dose-response manner. Application of the WHO anemia criteria in men may miss patients with mild anemia that places them at DCD risk. Further research should look at anemia as a cause of reversible dementia.

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BACKGROUND: In 2005, Clalit Health Services (CHS), the largest health maintenance organization in Israel, initiated an intervention program aimed at reducing the prevalence rate of infantile anemia (IA). This study evaluated the progress made during the intervention (2005-2014) and its yield 5 years after it ended (2019). METHODS: The CHS database was retrospectively reviewed twice yearly from 2005 to 2014 for repetitive samples of children aged 9 to 18 months regarding the previous half-year interval, and a single sample in 2019. Data were collected on gender, ethnicity (Jewish/non-Jewish), socioeconomic class (SEC; low/intermediate/high), hemoglobin testing (yes/no), and hemoglobin level (if tested). Excluded were infants with documented or suspected hemoglobinopathy. RESULTS: At study initiation, the rate of performance of hemoglobin testing was 54.7%, and the IA prevalence rate was 7.8%. The performance rate was lower in the Jewish than the non-Jewish subpopulation. The low-SEC subpopulation had a similar hemoglobin testing rate to the high-SEC subpopulation but double the IA prevalence rate. Overall, by the end of the intervention (2014), the performance rate increased to 87.5%, and the AI prevalence rate decreased to 3.4%. In 2019, there was little change in the performance rate from the end of the intervention (88%) and the IA prevalence was further reduced to 2.7%. The non-Jewish and low-SEC subpopulations showed the most improvement which was maintained and even bettered 5 years after the intervention ended. CONCLUSIONS: The 10-year IA intervention program introduced by CHS in 2005 led to a reduction in IA prevalence rate to about 3.5% in all sub-populations evaluated. By program end, the results in the weaker subpopulations, which had the highest prevalence of IA at baseline, were not inferior to those in the stronger subpopulations. We recommended to the Israel Ministry of Health to adopt the intervention countrywide, and we challenge other countries to consider similar interventions.

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BACKGROUND: The association between proton pump inhibitor (PPI) use and increased risk of dementia is controversial. AIM: Investigating this issue in a large population of community-dwelling elders. METHODS: Our database was retrospectively searched for all community-dwelling patients aged ≥65 years who newly diagnosed with dementia/cognitive decline (DCD) between January 2002 - December 2012. Receiving ≥11 prescriptions of PPIs/year was categorized as PPI users. Clinical data were collected from the medical files. Risk of DCD in PPI users was analyzed by Cox regression models. RESULTS: Included 48,632 elders of whom 8,848 were diagnosed with DCD (18.2%). PPI use was documented in 10,507, of whom 1,959 were subsequently diagnosed with DCD (18.6%). Among 38,125 non-PPI users, 6,889 (18.1%) were diagnosed with DCD. The hazard ratio for occurrence of DCD in PPI users compared to non-users was 0.85 (95% CI: 0.81-0.89, P <0.001) in an un-adjusted Cox regression model and 0.83 in a Cox regression model adjusted for age and sex (95% CI: 0.79-0.87, P <0.001). Multivariate Cox regression accounting for background diseases, marital status, and socioeconomic state yielded a hazard ratio of 0.77 (95% CI: 0.73-0.81, P <0.001). CONCLUSION: PPI use wasn't associated with DCD development in chronic PPI users.

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OBJECTIVES: To evaluate the sex-specific effects of stimulants in children with attention-deficit/hyperactivity disorder (ADHD) on body mass index (BMI) z and height z trajectories. STUDY DESIGN: A retrospective cohort study using the database of Israel Clalit Health Services was performed. Participants included 5- to 18-year-old insured patients with documentation of at least 2 consecutive prescriptions of stimulant drugs for ADHD. Participants were further compared with sex- and age-matched insured control patients without ADHD. RESULTS: A total of 4561 (66% boys) participants with ADHD were included. Of these, 2151 (70% boys) had follow-up data for ≥2 years of treatment. A decline of ≥1 SD in height and BMI z score was observed in 10.1% and 13.2% of the cohort, respectively. During ≥2 years follow-up, boys had a greater decline in height z score (~0.2 SD) than girls (~0.06 SD). Boys' height z score continued to decline after 1 and ≥2 years, and girls' height z score declined after 1 year, and then stabilized. The trajectory of BMI z score of boys and girls was similar, showing a greater decline after 1 year, followed by an incline after ≥2 years. Younger age at stimulants initiation, better adherence, longer treatment duration, and lower socioeconomic status were correlated with a greater impact on growth attenuation. The non-ADHD group (n = 4561, 66% boys) had baseline height z score and BMI z score similar to those in children with ADHD before treatment initiation. Height z score and BMI z score were greater in children without ADHD compared with children with ADHD following 1 year of treatment (P < .001). CONCLUSIONS: These findings highlight the importance of growth monitoring accompanied with dietary counseling in children with ADHD treated with stimulants.

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BACKGROUND: Evaluation of children's anthropometrics poses challenges due to age-related changes. The main focus is on height and weight. However, since weight is height-dependent, body mass index (BMI) is the best surrogate measurement of adiposity. Israel has not developed national growth tables; therefore, researchers and clinicians utilize either World Health Organization (WHO) or U.S. Centers for Disease Control and Prevention (CDC) tables as benchmarks. OBJECTIVES: To evaluate the anthropometrics of Israeli children benchmarked by CDC and WHO tables. METHODS: A retrospective review was conducted of the 1987-2003 birth cohort (age 4-18 years) from Clalit Health Services databases. Anthropometrics were retrieved twice: at study entry and one year later. We evaluated them as separate cohorts. Gender-specific age-matched median height and BMI were compared with CDC and WHO height and BMI tables. RESULTS: he study consisted of 15,650, mean age at study entry 9.5 years (range 4-18). Gender-specific median heights of the Israeli children were similar to CDC and WHO values at younger ages, but were slightly shorter than the age-matched CDC and WHO toward the age of final height in both cohorts. However, gender-specific median BMI was considerably and statistically significant higher compared to CDC and WHO values consistently along the entire age range in both cohorts. CONCLUSIONS: Israeli children were slightly shorter toward the age of final height, compared to WHO and CDC. However, BMI in Israeli children was significantly higher compared to the CDC and WHO consistently along the age range, which raises an alarm regarding obesity patterns.

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AIM: Data on cardiovascular outcomes in elderly using proton pump inhibitors (PPI) are scant. We aimed to test the association between PPI use and the occurrence of first-time ischemic stroke (FTIS) among elderly. METHODS: The electronic database of a centrally located district branch of a large health maintenance organization in Israel was retrospectively screened (2002-2016) for community-dwelling individuals (≥65-95 years) for demographics and co-morbidities. Follow-up was until FTIS, death or end of study. Findings were analyzed by PPI use and occurrence of FTIS. RESULTS: 29,639 subjects (without history of stroke and use of antiplatelet aggregation drugs) mean age of 82.2 ± 5.5 years (range: 65-95 years, 38% male) were analyzed: 8,600 (29%) used PPIs. Mean follow up was 10.58 years (SD ± 5.44). Similar total and annual occurrence rates of FTIS were depicted in PPI users and non-users (20.9% vs. 21% and 2% vs. 2.1%, respectively). On a Cox regression analysis, upon adjustment for age, gender and cardiovascular disease related risk factors, PPI use was significantly associated with lower rates of FTIS (HR 0.73, 95% C.I. 0.69-0.77, p < 0.001). The risk for FTIS was significantly lower in subjects using PPI at any dose and for any time period compared to non-users (HR 0.9, 95% C.I. 0.85-0.96 for 7-48 yearly prescriptions and HR 0.51, 95% C.I. 0.46-0.55 for ≥49 yearly prescriptions). CONCLUSIONS: PPI use was associated with lower rates of FTIS in community-dwelling elders. Prospective large-scale studies are needed to fully elucidate the effect of PPI in this aging population.

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BACKGROUND: The global incidence of thyroid cancer (TC) has risen considerably during the last three decades, while prognosis is generally favorable. We assessed the long-term all-cause mortality in TC survivors compared to the general population, and its association with cardiovascular risk factors. METHODS: Individuals diagnosed with TC during 2001-2014 (TC group) and age- and sex-matched individuals from the same Israeli healthcare system without thyroid disease or a cancer history (non-TC group) were compared. Cox regression hazard ratios (HRs) and 95% confidence intervals (95%CIs) for all-cause mortality were calculated by exposure status. RESULTS: During a 15-year follow-up (median 8 years), 577 TC survivors out of 5677 (10.2%) TC patients and 1235 individuals out of 23,962 (5.2%) non-TC patients died. The TC survivors had an increased risk of all-cause mortality (HR = 1.89, 95%CI 1.71-2.10), after adjusting for cardiovascular risk factors already present at follow-up initiation. This increased risk was most pronounced in the 55- to 64-year-old age group (HR = 1.49, 95%CI 1.33-1.67). The TC survivors who died by study closure had more hypertension (14.6% vs. 10.3%, P = 0.002), more dyslipidemia (11.4% vs. 7.2%, P <  0.001), and more cardiovascular disease (33.6% vs. 22.3%, P = 0.05) compared to those who died in the non-TC group. CONCLUSIONS: This large cohort study showed higher all-cause mortality with a higher prevalence of hypertension, dyslipidemia, and cardiovascular disease among TC survivors compared to matched non-TC individuals. Primary and secondary prevention of cardiovascular risk factors in TC survivors is mandatory.

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Alterations in thyroid hormone levels may affect brain and mental disorders. Conversely, schizophrenia and its antipsychotic treatments can affect thyroid hormone levels. However, data on thyroid hormone levels during the course of schizophrenia disorder are scant. The aim of the study was to assess the rate of thyroid hormone disorders in outpatients before and after diagnosis of schizophrenia. A retrospective matched-control design was used. The cohort included 1252 patients suffering from ICD-10 schizophrenia, and 3756 control subjects matched for gender, age, socioeconomic status, and origin. All were identified from the database of a large health management organization. The pertinent clinical data were collected from the electronic medical records. There was no significant between-group difference in the distribution of thyroid-stimulating hormone levels. Before diagnosis, both groups had a similar rate of hypothyroidism. After diagnosis of schizophrenia and initiation of antipsychotic treatment, the rate of hypothyroidism was significantly higher in the patient group. It remained significantly higher after exclusion of patients receiving lithium. The increased rate of hypothyroidism in patients with schizophrenia after, but not before, the diagnosis of schizophrenia suggests that antipsychotic medications may affect thyroid hormone levels. Screening for thyroid disorders is warranted in patients with schizophrenia under antipsychotic treatment.

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OBJECTIVE: The need for personalization of the reference values of thyroid function tests has been previously suggested. We aimed at determining TSH reference values in a large cohort of children according to age, sex, BMI, and ethnicity. DESIGN: A population-based cohort study. METHODS: The study cohort included 75 549 healthy children aged 5-18 years. Data analyzed included age, gender, TSH, FT4 levels, BMI and ethnicity. Multivariate logistic regression analysis examined the associations between the study parameters. RESULTS: TSH in the Jewish population is lower than in the non-Jewish population (median: 2.1 IU/L (IQR: 1.5) vs 2.2 IU/L (IQR: 1.5), P < 0.0001). TSH is significantly affected by BMI for children defined as underweight, normal weight, overweight or obese, levels increased as weight diverged from the normal range (median levels: 2.1 IU/L (IQR: 1.4), 2.0 IU/L (IQR: 1.3), 2.1 IU/L (IQR: 1.4), 2.4 (IQR: 1.5), respectively, P < 0.001). The 2.5 percentile is affected by gender and BMI (P < 0.02 and P < 0.001, respectively), while the 97.5 percentile is affected by ethnic origin and BMI (P < 0.001 for both). New TSH reference intervals (RI) adjusted according to BMI and ethnicity are suggested. Comparison of the old and new RI demonstrate the significance of RI personalization: 25.1% of the children with TSH levels above the old RI are within the new RI, while 2.3% of the children who were in the old RI are below the new RI. CONCLUSIONS: TSH reference values in children are affected by BMI and ethnicity. Reference values should be individualized accordingly to improve future clinical decision-making and treatment.

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Increasing numbers of children with developmental, emotional, and psychosocial issues require adaptation of the services provided by pediatricians in the community. An international workshop that took place in Israel on June 3-4, 2019, addressed this need. Local policy makers and international experts discussed the following topics: (1) the future of training in community pediatrics; (2) enhancing the prestige of the community pediatrician; (3) development of management and research skills; (4) academic advancement within community pediatrics; (5) the future content of community pediatric practice; (6) visit length and community pediatricians' reimbursement; (7) developing the collaborative model of care in community pediatrics and (8) integrating child healthcare. The meeting provided a venue to understand the challenges and to formulate recommendations to policymakers. A key target highlighted was the increased exposure of all pediatric residents to community pediatrics. This gained the support of the Chief Executive Officers of all four Health Funds in Israel. This document provides a synopsis of the topics addressed and suggested recommendations.

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This study sought to determine the prevalence of significant liver disease in those subjects with serum alanine aminotransferase levels in the range between the current and the newly suggested upper limit of normal (termed the delta range). The files of the previous study subjects (who underwent at least one alanine aminotransferase measurement in 2002 and followed to 2012) were reviewed for a diagnosis of chronic liver disease; aspartate aminotransferase/platelet ratio index, FIB-4 and alanine aminotransferase/aspartate aminotransferase ratio were used to evaluate liver fibrosis. The prevalence of significant liver disease, by diagnoses and fibrosis scores was compared between subjects with alanine aminotransferase levels in the delta range (men, 42-45 IU/L; women, 26-34 IU/L) and in the newly suggested normal range (men, 15-42 IU/L; women, 10-26 IU/L). The cohort included 49,634 subjects (41% male, mean age 83±6 years) of whom 2022 were diagnosed with chronic liver disease including 366 with cirrhosis. Compared to subjects with alanine aminotransferase levels in the newly suggested normal range, subjects with alanine aminotransferase levels in the delta range had a significantly higher rate of chronic liver disease (men, 15.3% vs. 4.9%; women, 7.8% vs. 3.3%) and of cirrhosis specifically (men, 4.2% vs. 0.9%; women, 1.5% vs. 0.4%) and also had higher mean fibrosis scores (P <0.001 for all). Lowering the current upper limit of normal of serum alanine aminotransferase may help to identify elderly patients at risk of significant liver disease.

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CONTEXT: Management of GH-treated children with idiopathic short stature (ISS) with early puberty and adolescents in midpuberty at initiation of treatment is challenging. OBJECTIVE: To assess the effect of combined GH/GnRHa therapy during puberty on achieved adult height (AHt) in these children with ISS and to determine whether outcome depended on sex and pubertal status at initiation of GH therapy. DESIGN: Retrospective, single-center observational study from 2003-2018. SETTING: Tertiary endocrine center. PATIENTS: One hundred ninety-two GH-treated children with ISS; 58 of 192 were treated by GH/GnRHa during puberty; 31 of 58 were prepubertal (19 girls) and 27 of 58 pubertal (19 girls) at initiation of GH. MAIN OUTCOME MEASURES: AHt, gain-in-height standard deviation score (SDS), AHt vs predicted adult height (PAHt), AHt vs target height (THt). RESULTS: Most boys and girls attained AHt SDS within the normal range (-0.73 ± 0.60 and -0.85 ± 0.65, respectively). Treatment modality, pubertal status, and sex were tested for their joint effect on growth outcome measures. Combined GH/GnRHa therapy increased AHt vs PAHt (P < 0.001) and AHt vs THt (P = 0.035). Prepubertal status at onset of GH treatment increased AHt (P = 0.049), gain-in-height SDS (P < 0.001), AHt vs PAHt (P < 0.001), and AHt vs THt (P = 0.042). Female sex increased AHt vs PAHt (P < 0.001). CONCLUSIONS: Our study demonstrated a beneficial effect of combined GH/GnRHa therapy in increasing AHt outcome in children with ISS with early/normal puberty and in adolescents naïve to GH treatment who are in midpuberty at initiation of therapy. This effect was more pronounced in the prepubertal group and in girls. Prospective randomized controlled trials are needed to assess whether GnRHa can increase AHt in GH-treated children with ISS.

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OBJECTIVE: Thyroid cancer (TC) survivors may be at risk of subsequent cardiovascular and cerebrovascular (CaV&CeV) morbidity. The 2009 American Thyroid Association (ATA) guidelines recommended less aggressive treatment for low-risk TC patients. The aim of this study was to assess the atherosclerotic CaV&CeV outcome of Israeli TC survivors compared to individuals with no thyroid disease, and the atherosclerotic CaV&CeV outcome before (2000-2008) and after (2009-2011) implementation of the 2009 ATA guidelines. METHODS: All members of the largest Israeli healthcare organization who were diagnosed with TC from 1/2000 to 12/2014 (study group) and age- and sex-matched members with no thyroid disease (controls) were included. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated using Cox proportional hazards models. RESULTS: The mean follow-up was 7.6 ± 4.2 and 7.8 ± 4.1 years for the study (n = 5,677, 79% women) and control (n = 23,962) groups, respectively. The former had an increased risk of new atherosclerotic CaV&CeV events (adjusted HR 1.26, 95% CI 1.15-1.39). The 5-year incidence of CaV&CeV was lower (adjusted HR 0.49, 95% CI 0.38-0.62) from 2009 to 2011 compared to 2000 to 2008, but remained higher in the study group than in the control group (adjusted HR 1.5, 95% CI 1.14-1.69). CONCLUSIONS: This large Israeli population-based cohort study showed greater atherosclerotic CaV&CeV morbidity in TC survivors compared to individuals with no thyroid diseases. There was a trend toward a decreased 5-year incidence of atherosclerotic CaV&CeV events among TC survivors following the implementation of the 2009 ATA guidelines, but it remained higher compared to the general population.

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OBJECTIVE: Adherence to treatment regimen is a key factor in the success of Growth Hormone (GH) therapy. Our objective was to assess the long time adherence to treatment in a large cohort of patients. DESIGN: It is a retrospective study. The data was collected from a single central computerized data center well maintained and checked for quality. All patient aged 1-16 years, treated with GH during 2006-2015 for >2 years, who were insured by "Clalit" Health Maintenance Organization. Adherence was measured by the number of months of pharmacy purchased GH annually: good (11-12), moderate (7-10), and poor (<7) months per year. RESULTS: 2263 patients (59% males) were treated for >2 years. Mean age at treatment initiation was 8.3 ±â€¯3.6 years, 74% were secular Jews, 6.8% ultra-religious Jews and 18.9% of Arab origin. Only 30% of patients had good adherence to GH therapy. Patients who started treatment before age 8 years had poorest adherence rate. No association was found between adherence to GH therapy and gender or socioeconomic status. In a multivariate analysis (gender, age groups, ethnicity and clinic SES) we found the ultra-religious population had higher risk for non adherence (OR 2.16, CI 95% 1.46-3.19). The poorest adherence by age was in the youngest patients. In patients treated for >5 years (n = 668), adherence rate declined slightly over the years. CONCLUSIONS: Long term adherence to GH therapy is suboptimal. Measures for improving adherence especially among younger and ultra- religious patients are needed.

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